| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Rheumatoid arthritis in patients who have failed to respond to an initial TNF-blocking drug |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced rheumatoid arthritis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare an alternative TNF-blocker or abatacept with NICE-approved rituximab in patients with rheumatoid arthritis who have failed an initial Tumour Necrosis Factor (TNF) blocking drug. |
|
| E.2.2 | Secondary objectives of the trial |
| To compare an alternative TNF-blocker or abatacept with rituximab in terms of quality of life, toxicity and safety and whether these specific therapies can be targetted to disease sub-groups. The SWITCH study will also evaluate the cost-effectiveness of switching patients to an alternative TNF-blocker, abatacept or rituximab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients meeting all of the following criteria will be considered for enrolment into the study:
1. Male and female subjects aged ≥18 years at the time of signing the Informed Consent Form.
2. Patients with a diagnosis of rheumatoid arthritis as per the ACR/EULAR 2010 classification criteria (Appendix 7) confirmed at least 24 weeks prior to the screening visit.
3. Patients who have failed conventional DMARD therapy as per NICE/BSR Guidelines (49) i.e. failure of at least 2 DMARDS including MTX.
4. Patients with persistent RA disease activity despite having been treated with a current initial TNFi agent for at least 12 weeks. Active RA defined as*:
a. Primary non-response: failing to improve DAS28 by > 1.2 (Appendix 6) or failing to achieve DAS28 ≤ 3.2 within the first 12 to 24 weeks of starting the initial TNFi.
• This may include patients that have shown a reduction in DAS28 of > 1.2 but still demonstrate unacceptably high disease activity in the physician’s judgement with evidence of an overall DAS28 of >/= 3.2
OR
b. Secondary non-response: defined as inefficacy to first TNFi (having demonstrated prior satisfactory response) as per clinician judgement; with intolerance not the reason for cessation of first TNFi.
*These criteria are consistent with BSR guidelines (49).
5. MTX dose stable for 4 weeks prior to the screening visit and to be continued for the duration of the study.
6. Patients on NSAIDs and / or corticosteroids (oral prednisolone not exceeding 10mg daily) who have been on an unchanged regimen for at least 4 weeks prior to the screening visit and are expected to remain on a stable dose until the baseline assessments have been completed.
7. Provided written informed consent prior to any trial-specific procedures.
|
|
| E.4 | Principal exclusion criteria |
Patients will be excluded from this study for any of the following reasons:
General
1. Major surgery (including joint surgery) within 8 weeks prior to the screening visit or planned major surgery within 52 weeks following randomization.
Study Specific
2. Patients with inflammatory joint disease of different origin, mixed connective tissue disease, Reiter’s syndrome, psoriatic arthritis, systemic lupus erythematosus, or any arthritis with onset prior to 16 years of age.
3. Patients receiving doses of prednisolone > 10mg/day within the 4 weeks prior to the screening visit.
4. Patients receiving intra-articular or intra-muscular steroid injections within 4 weeks prior to the screening visit.
Excluded Previous or Concomitant Therapy:
5. Patients who have previously received more than 1 TNFi drug OR any other biological therapy for the treatment of RA.
6. Patients unable or unwilling to stop treatment with a prohibited DMARD (i.e synthetic DMARD aside from MTX e.g. oral or injectable gold, chloroquine, hydroxychloroquine, cyclosporine, azathioprine, leflunomide, sulphasalazine) prior to the start of protocol treatment.
7. Treatment with any investigational drug in the last 12 weeks prior the start of protocol treatment.
Exclusions for general safety
These criteria should be considered in the context of BSR guidance (49).
8. Patients with other co-morbidity including acute, severe infections, uncontrolled diabetes, uncontrolled hypertension, unstable ischaemic heart disease, moderate/severe heart failure (Class III/IV of the New York Heart Association (NYHA) functional classification system (79)), active bowel disease, active peptic ulcer disease, recent stroke (within 12 weeks before the screening visit), or any other condition which, in the opinion of the investigator, would put the patient at risk to participate in the study or would make implementation of the protocol difficult.
9. Patients with any major episode of infection requiring hospitalisation or treatment with IV antibiotics within 12 weeks of start of treatment protocol or oral antibiotics within 4 weeks of start of protocol treatment.
10. Patients at significant risk of infection, which in the opinion of the investigator would put the patient at risk to participate in the study (e.g. leg ulceration, indwelling urinary catheter, septic joint within 52 weeks (or ever if prosthetic joint still in situ)).
11. Patients with known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections including herpes zoster (for tuberculosis and Hepatitis B and C see below), but excluding fungal infections of nail beds as per clinical judgment.
12. Patients with untreated active current or latent tuberculosis (TB). Patients should have been screened for latent TB (as per BSR guidelines) within 24 weeks prior to the screening visit and, if positive, treated following local practice guidelines prior to the start of protocol treatment.
13. Patients with active current hepatitis B and/or C infection. Patients should have been screened for hepatitis B and C within 24 weeks prior to the screening visit and if positive, excluded from the study.
14. Primary or secondary immunodeficiency (history of or currently active) unless related to primary disease under investigation.
15. Pregnancy, lactation or women of child-bearing potential (WCBP) unwilling to use an effective birth control measure (Appendix 2) whilst receiving treatment and after the last dose of protocol treatment as indicated in the relevant SmPC/IB.
16. Men whose partners are of child-bearing potential but who are unwilling to use an effective birth control measure (Appendix 2) whilst receiving treatment and after the last dose of protocol treatment as indicated in the relevant SmPC/IB.
Laboratory value exclusions
17. Patients with known significantly impaired bone marrow function as for example significant anaemia, leukopaenia, neutropaenia or thrombocytopaenia as shown by the following laboratory values at the time of the screening visit:
• Haemoglobin < 8.5 g/dl
• Platelet count < 100 x 109 / L
• White blood cell count < 2.0 x 109 / L
• Neutrophil count < 1 x 109 / L
18. Patients with known severe hypoproteinaemia at the time of the screening visit, e.g. in nephrotic syndrome or impaired renal function, as shown by:
• Serum Creatinine > 150 umol / L
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change in Disease Activity Score 28 (DAS28) at 6 months (24 weeks). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• DAS28
o Proportion of patients who achieve a reduction in DAS28 score of greater than 1.2 with no toxicity.
o DAS28 Score
o Low Disease Activity (LDA) Rate and Remission Rate
• EULAR Response Scores and American College of Rheumatology (ACR) Response Scores
• CDAI (Clinical disease activity Index)
• SDAI (Simplified Disease Activity Index)
• ACR/EULAR Boolean remission rates
• Quality of Life Assessments
o RA Quality of Life (RAQoL) score
o Health Assessment Questionnaire Disability Index (HAQ-DI©)
o Hospital Anxiety and Depression Scale (HADS)
• Safety and Toxicity
o Adverse Events and Reactions
• Economic Evaluation
o EuroQol 5-dimensions (EQ-5DTM)
o Health Utilities Index
o Health and Social Care Use & Expenditure due to Rheumatoid Arthritis
o Incremental Cost Effectiveness
• Imaging (at the discretion of individual sites)
o Change in plain x-ray score of hands and feet (Modified Genant score)
o Bone densitometry scan scores (T-scores unilateral neck of femur and lumbar spine)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints will be measured at baseline and at weeks 12, 24, 36 and 48 except the following:
• Quality of Life Assessments
o Health Assessment Questionnaire Disability Index (HAQ-DI©) (also evaluated at weeks 60, 72, 84 and 96)
• Economic Evaluation
o EuroQol 5-dimensions (EQ-5DTM) (also evaluated at weeks 60, 72, 84 and 96)
o Health Utilities Index (also evaluated at weeks 60, 72, 84 and 96)
• Imaging (at the discretion of individual sites)
o Change in plain x-ray score of hands and feet (Modified Genant score - evaluated at baseline and week 48)
o Bone densitometry scan scores (T-scores unilateral neck of femur and lumbar spine- evaluated at baseline and week 48) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 30 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the trial is defined as the date of last data collection for the last patient randomised to the trial. This is planned for 12 months following the date the last participant is randomised to the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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